CA2166988A1 - Novel dialkoxy-pyridinyl-benzimidazole derivatives - Google Patents
Novel dialkoxy-pyridinyl-benzimidazole derivativesInfo
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- CA2166988A1 CA2166988A1 CA002166988A CA2166988A CA2166988A1 CA 2166988 A1 CA2166988 A1 CA 2166988A1 CA 002166988 A CA002166988 A CA 002166988A CA 2166988 A CA2166988 A CA 2166988A CA 2166988 A1 CA2166988 A1 CA 2166988A1
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- Prior art keywords
- methyl
- pyridinyl
- carbomethoxy
- benzimidazole
- sulfinyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The novel optically pure compounds, i.e. the single enantiomeric compounds, (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-<u>H</u>-benzimidazole and (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-<u>H</u>-benzimidazole or a therapeutically acceptable salt thereof, such as Na+, Mg2+, Li+, K+, Ca2+ and N+(R)4 salts, where R is an alkyl group with 1-4 carbon atoms, processes for the preparation thereof and pharmaceutical preparations containing the compounds as active ingredients, as well as the use of the compounds in pharmaceutical preparations and intermediates obtained by preparing the compounds.
Description
~ ~6~
NOVEL DIALKOXY-PYRIDINYL-BENZIMIDAZOLE DER~VATIVES
Field of the invention 5 The present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation. The invention also relates to novel intermediates in the preparation of the compounds of the invention.
Ba~ k~round of theinvention The compound 5-carbomethoxy-6-methyl-2-[[(3,~dimethoxy-2-pyridinyl)methyl]sulfinyl]-1~ benzimidazole, and therapeutically acceptable salts 15 thereof are described in application number EP 91911618.6. This compound and its therapeutically acceptable salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents. The compounds, being sulfoxides, have an asymrnetric center in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved 20 pharmacokinetic and metabolic properties which will give an improved therapeutic profile. The present ~ /enlion provides such compounds, which are novel salts of single enantiomers of 5-carbomethc-xy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1~ benzimidazole as well as the novel single enantiomers of the neutral form of said compound.
The separation of the enantiomers of therapeutically active sulfoxides, such as substituted ben7imi~1a70l~, for example omeprazole (5-methoxy-2-[[(~methoxy-3,5 dimethyl-2-pyridinyl)methyl]sulfinyl~ ben7imi~la7ole) in analytical scale isdescribed in e.g. J. Chromatography, 532 (1990), 30~19. The isolation of single 30 enantiomers of the sulfoxide agent Ro 18-5364 is described in Euro. J. Biochem. 166 `' (1987) 453-459. Furthermore, separation of the enantionlPr~ of omeprazole in a preparative scale is ~le~ rihed in DE 4035455. The latter has been done by using a diastereomeric ether which is separated and thereafter hydrolysed in an acidic solution. Under the acidic conditions needed for hydrolysis of the attached group, 35 the active compound, omeprazole, is quite sensitive and the acid has to be quickly WO 95/32959 ~ 1 ~ 6 ~ 2 PCT/SE95/00519 neutralized with a base to avoid degradation of the acid-sensitive compound. In the above mentioned application this is done by adding the reaction mixture containing concentrated sulfuric acid to a concentrated solution of NaOH. This is disadvantageous because there is a great risk of locally reaching pH values 5 between 1-6, which would be devastating for the substance. Moreover, instantaneous neutralization will create heat which will be difficult to handle in large scale production.
The present invention in a further aspect provides a novel method for preparing 10 the novel compounds of the invention in large scale. Thus, this novel method can be used in large scale to obtain single enantiomers of the compound of the invention in neutral form, as well as in the form of the therapeutically acceptable salts.
15 These novel compounds of the invention, being sulfoxides, could be expected to undergo racemization in neutral pH as well as in basic pH. See for example Brandstrom et al, Acta Chemica Scandinavia 43 (1989) p.536-547. Surprisingly, the inventors now found that the novel single enantiomers of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH ber~7imi~1~701e as well 20 as its therapeutically acceptable salts are stable towards racemi_ation.
There is no example known in the prior art of any isolated or characterized single enantiomers of the compound of the invention. Furthermore, the inventors are notaware of any description in the scientific literature of any isolated salt of a single 25 enantiomer of the rl~ime~l type.
Detailed description of the invention 30 The present invention refers to the new single enantiomers of 5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH benzimidazole according to compounds Ia and lb 6~g8~
~OCH3 I~N~CH2--~/ ~COOCH3 ~I Ib) r CH3 H
Ia (+)-enantiomer Ib (-)-enantiomer as well as therapeutically acceptable salts thereof. Such salts are for example the Na+, Mg2+, Ca2+, Li+, K+ and N+(R)4 salts of the single enantiomers of said compound, where R is an alkyl group with 1-4 carbon atoms, i.e. (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH
10 benzimidazole and (-)-5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH benzimidazole as well as Na+, Mg2+, Ca2+, Li+, K+
and N+(R)4 salts of the single enantiomers, where R is an alkyl group with 1-4 carbon atoms.
15 Particularly ~refel,~d salts of the compound of the invention are the Na+, Mg2+
and Ca2~~ salts of the single enantiomers of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole.
The mosl: preferred compounds of the invention are the optically pure 5-20 carbomethoxy-~methyl-2-[[(3,~dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH
benzimidazole according to the above formulas Ia and Ib. Further ~r~fe.led compounds are the optically pure Na+ salts of 5 carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole according to compounds IIa and Il[b W095t32959 ~G~ 4 PCT/SE95/OOS19 ~CH3 ~,OCH3 I~N~CH2--S~/ ~[~COOCH3 ~a IIb) Na+
IIa (+)-enantiomer IIb (-)-enantiomer 5 and the optically pure magnesium salts of said compounds having the formulas ma and IIIb.
~,OCH3 I~N~CH2--S~/ ~COOCH3 ~ma mb) Mg2+
ma (+)-enantiomer IIIb (-)-enantiomer With the expression "optically pure compound of the invention" is meant the (+)-enantiomer of said compound essentially free from the col,e~onding (-)-15 enantiomer and the (-)-enantiomer essentially free from the co~re~onding (+)-enantiom~r, respectively. Thus, every single compound of the invention is obtained in high optical purity. By means of the novel specific method accordingto one aspect of the invention of preparing the single enantiomers, the compounds of the invention are easy to obtain. Moreover, as mentioned above the novel 20 optically pure compounds are stable towards racemization in neutral pH as well as basic pH. The former was surprising since the mechanism of the degradation reactions at neutral pH of these kind of sulfoxides (omeprazole analogues) contains reversible reactions via achiral interme~liAtes (see e.g. Brandstrom et al.
Acta Chemica Scandinavica 43 (1989) 53~547, especially p.538). It is obvious that 25 such reversible reactions from achiral int~ liAtes back to a sulfoxide would 2~ I 6 6 ~ g ~ PCT/SE95/00519 cause a racemic product. Further, the novel optically pure compounds are stable towards racemization in basic pH, which was surprising sirlce the known deprotonation at the carbon atom between the pyridine ring and the chiral sulphur atom was expected to cause racemization under alkaline conditions. This 5 high stability towards r~c~mi7~tion, both in neutral pH and basic pH, makes itpossible to use a single enantiomeric compound of the invention in the neutral form as well as salts thereof in therapy.
The specific method of preparation of the single enantiomers of the compound of 10 the invention is a further aspect of the invention as mentioned above and it can be used to obtain the single enantiomeric compounds in the neutral form as well as the salts thereof.
The single enantiomeric compounds of the invention as well as the racemate have 15 a high level of bioavailability, and does not block the uptake of iodine into the thyroid gland, and still said compounds are very effective as inhibitors of gastric acid secretion and exhibit high stability properties at neutral pH.
The compounds according to the invention may be used for inhibiting gastric acid20 secretion in nl~mm~l~ and man. In a more general sense, the single enantiomeric compounds of the invention may be used for the treatment of gastric acid-relateddiseases and gastrointestinal inflammatory diseases in ~mm~l~ and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis. Furthermore, the compou~nds may be used for treatment of other gastrointestinal disorders where 25 gastric antise~leloly effect is desirable e.g. in patients on NSAID therapy, in patients with gastrinomas, and in patients with accute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration. The compourld of the invention may also be used for treatment or prophylaxis of 30 inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be sepcifically mentioned are rheumatoid arthritis and gout. The compound of the invention may also be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections.
35 Yet a further aspect of the invention is the diasteromeric mixture of a regioi~omeric mixture having the formula IV, which is an intermediate used in the WO 95132959 ~ 6 PCT/SE95/00519 specific method of preparation, wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in the 5 or 6 position, respectively.
,OCH3 ~,OCH3 I~N~CH2--S~/ ~COOCH3 N CH3 (IV) O
Preparation The optically pure compounds of the invention, i.e. the single enantiomers, are prepared by separating the stereoisomers of a diastereom~ric mixture of the 10 regioisomeric mixture of the following type, 5-carbomethoxy-6-methyl-2-[[(3,~
dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-l(R)-acyloxymethyl-lH-be~7imi~ole and 6-carbomethoxy-5-methyl-2-[[(3,~dimethoxy-2-pyridinyl)methyl]-(R/s)-sulfinyl]-l-[(R)-acyloxymethyl-l~I-benzimidazole formula V
~,OCH3 I~N~CH2--S~/ ~ COOCH3 N CH3 (V) CH2--OAcyl wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in position 5 or 6, respectively, and wherein the Acyl radical is as defined20 below, followed by a solvolysis of each separated diastereomer in an alkalinesolution. The formed single enantiomeric compounds of the invention in neutral form are then isolated by neutralizing aqueous solutions of the salts of said wo 9s/32959 7 ~ ~ ~ 6 ~ ~ ~ PCT/SE95/00519 compounds with a neutralizing agent which can be an acid or an ester such as methyl formate.
The Acyl moiety in the diastereomeric ester may be a chiral acyl group such as 5 mandeloyl, and the asymmetric center in the chiral acyl group can have either R or S configuration.
The diastereomeric esters can be separated either by chromatography or fractional crystallization.
The solvolysis usually takes place together with a base in a protic solvent such as alcohols or water; or with a base in a mixture of acetonitrile and water, but the acyl group may also be hydrolysed off by a base in an aprotic solvent such as dimethylsulfoxide or dimethylformamide. The reacting base may be OH- or R1O-15 where R1 can be any alkyl or aryl group.
To obtain the optically pure Na+ salts of the invention, i.e. Na+ salts of the s ingleenantiomeric compound of the invention, the resulting compound in neutral form is treated with a base, such as NaOH, in an aqueous or nonaqueous medium, or 20 with NaOR2 wherein R2 is an alkyl group containing 1-4 carbon atoms, or with NaNH2. Also alkaline salts wherein the cation is Li+ or K+ may be prepared usinglithium or potassium salts of the above mentioned bases. In order to obtain the crystalli~e form of the single enar~tiom~rs of the Na+ salts, to the optically pure Na+ salts as a syrup are added a mixture of 2-butanone and toluene, but the 25 crystalline form of the single enantiomers of the Na+ salt may also be prepared by adding NaOH to a mixture of the single enantiomeric compound of invention and a non-aqueous medium, such as a mixture of 2-butanone and toluene.
To obtain the optically pure Mg2+ salts of the invention, optically pure Na+ salts 30 are treated with an aqueous solution of an inorganic magnesium salt such as MgC12, whereupon the Mg2+ salts are precipitated. The optically pure Mg2+ salts may also be prepared by treating single enantiomeric compound of the invention with a baLse, such as Mg(oR3)2, wherein R3 is an alkyl group containing 1-4 carbon atoms, ir~ a non-aqueous solvent such as alcohol (only for alcoholates), e.g. ROH, 35 or in an ether such as tetrahydrofuran. In an analogous way, also alkaline salts wherein the cation is Ca2+ can be prepared, using an aqueous solution of an inorganic c~ m~ salt such as CaCk.
wo 95/32959 ~ 5 8 PCT/SE9S/00519 Alkaline salts of the single enantiomers of the invention are, as mentioned above, beside the sodium salts (compounds IIa and IIb) and the magnesium salts (compound ma and mb), exemplified by their salts with Li+, K+, Ca2+ and N+(Rj4, where R is an alkyl group with 1-4 C-atoms.
Por clinical use the single enantiomers, i.e. the optically pure compounds, of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other modes of administrations. The pharmaceutical formulations contain the single enantiomers of the invention normally in combination with a 10 pharmaceutically acceptable carrier. The carrier may be in form of a solid, semi-solid or liquid diluent, or capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1-95% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1-50% by weight in preparations for oral 15 adrninistration. An active compound in a form with high solubility in water is requested for parenteral preparations, for some oral preparations an active compound in a form with low solubility is suitable.
In the preparation of pharmaceutical formulations in form of dosage units for oral 20 administration the single enantiomeric compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, c~ lose derivates, gelatin or another suitable carrier, stabilizingsubstances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating 25 agents such as magnesium stearate, c~l~ itlm stearate, sodium stearyl fumarate and polyethylenglycol waxes. The mixture is then processed into granules or pressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalysed degradation as long as the dosage form remair~s in the stomach. The enteric coating is chosen among 30 pharmaceutically acceptable enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers and the like, if ~reL~Lled in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different amounts of the active compound present.
35 Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound, vegetable oil, fat, or other suitable vehicle for soft gelatinecapsules. Soft gelatine capsules may also be enteric-coated as described above.
wo gs/3295g 9 2 ~ 8 8 PCT/SEg~/00519 Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, 5 mannitol, potato starch, amylopectin, cellulose derivates or gelatin. The capsules may be enteric-coated as described above.
Dosage ~nits for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or 10 they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to 15 administration.
Liquid preparation for oral administration may be prepared in the form of syrupsor suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight o~ the active ingredient and the remainder consisting of sugar or sugar 20 alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of dry powder to be reconstituted with a suitable solvent 25 prior to use.
Solutions for parenteral administrations may be prepared as solutions of the single enantiomeric compounds of the invention in pharmaceutically acceptable solvents, ~refelably in a concentration from 0.1 to 10% by weight. These soultions may also 30 contain stabilizing agents and/or buffering agents and may be manufactured indifferent unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as dry preparations to be reconsituted with a suitable solvent extemporaneously before use.
35 The typical daily dose of the active compound will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of acti~e substance.
The invention is illustrated by the follo~ring examples.
F.xample 1. Preparation of (+)-5-carbomethoxy-~methyl-2-~(3 4-dimethoxy-2-pvridinyl)methyl]sulfinyl]-lH-ben7.imidazole 10 The crude product of the diastereomers of a mixture of two regioisomeric mandelic esters, namely 5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-l(R)-mandeloyloxymethyl]-lH-benzimidazole and ~carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-lH-benzimidazole (1.8 g, 3.3 mmol) was 15 divided into three parts. Each part was chromatographed on a reversed phase column (HPLC, Kromasil C8) in order to separate the diastereomers. The stereoisomers were easily separated by elution with a mixture of aqueous 0.1 M
ammonium acetate and acetonitrile (70/30), but each separated diastereomer consisted of a mixture of the two regioisomers. These intermediates were used 20 directly in their solutions during the hydrolyses; To the acetonitrile/aqueous solutiorls of the more lipophilic diastereomer were added 1 M aqueous solutions of NaOH until the pH was around 12-13. After 5 minutes the solutions were neutralized with 3.0 M aqueous solutions of NH4Cl. The solutions from each preparation were combined and extracted with methylenechloride whereupon the 25 organic phases were dried over Na2SO4. Removal of the solvents and flash chromatography of the residue (silica gel, methanol-methylenechloride gradient 1-8%) yielded 250 mg of a yellow oil. The product was crystallised by adding acetonitrile (3 ml) and after filtration there was obtained 210 mg (32%) of the title compound as white crystals m.p. 171-173 C. [a]20 D= +153.1 (c=0.5%, 30 chlorofo~
NMR data are given below.
WO 95/32959 ~ fi ~ PCT/SE95/00519 E~xample 2. Preparation of (-)-5-carbomethoxy-~methyl-2-[[(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole To the acetonitrile/aqueous solutions of the less lipophilic diastereomer of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-l_-benzimidazole and 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-lH-benzimidazole (obtained from the very same reversed phase chromatographic preparations described in Example 1) were added 1.0 M NaOH until the pH was around 12-13. After 5 minutes the solutions were neutralized with 3.0 M aqueous solutions of NH4Cl. The solutions from each preparation were combined and extracted with methylenechloride whereupon the organic phases were dried over Na2SO4. Removal of the solvents and flash chromatography of the residue (silica gel, methanol-methylenechloride gradient 1-8%) yielded 270 mg of a yellow oil.
The product was crystallized by adding acetonitrile (3 ml) and after filtration there was obtained 210 mg (32%) of the title compound as white crystals m.p. 173-174 C. [a]20D= -150.0 (c=0.5%, chloroform).
NMR data are given below.
Fxample 3. Preparation of (+)-5-carbomethoxy-6-methyl-2-~(3.~dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-be~7imidazole sodium salt To a mixture of (+)-5-carbomethoxy~methyl-2-[[(3,~dimethoxy-2-pyridinyl)-methyl]sulfinyl]-l-~-benzimidazole (200 mg,0.51 mmol) and ethanol (10 ml) was added an aqueous solution of 2.0 M NaOH (0.26 ml, 0.51 mmol). The solvent wa removed by film evaporation whereupon the residue was dissolved in 2-butanone (1 ml). Toluene (5 ml) was added dropwise while stirring. The formed precipitatewas removed by centrifugation and washed with diethyl ether. There was obtained 170 mg (81%) of the title compound as white crystals m. p. (decomp.) 170-173C. [a]20D= +93.6(c=1%, methanol).
.
NMR data are given below g~ --Fxample 4. Preparation of (-)-5-carbomethoxy-~methyl-2-[[(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1~-benzimidazole sodium salt To a mixture of (-)-5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)-methyl]sulfinyl]-1-~-benzimidazole (200 mg, 0.51 mmol) and ethanol (10 ml) was added an aqueous solution of 2.0 M NaOH (0.26 ml, 0.51 mmol). The solvent was removed by film evaporation whereupon the residue was dissolved in 2-butanone (2 ml). Toluene (5 ml) was added dropwise while stirring. The formed precipitatewas isolated by filtration and washed with diethyl ether. There was obtained 200mg (96%) of the title compound as white crystals m. p. (decomp.) 172-175C.
[a]20D= -93.8 (c=1%, methanol).
NMR data are given below F~xample 5. Preparation of (+)-~carbomethoxy-~methyl-2-~[(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl~-lH-benzimidazole magnesium salt (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-~-benzimidazole sodium salt (100 mg, 0.24 mmol) obtained as in Example 3 was dissolved in water (2 ml) and MgCkx6H20 (25 mg, 0.12 mmol) dissolved in water (1 ml) was added dropwise. The formed precipitate was isolated by centrihlgationand washed with water. The product was dried in a desiccator and there was obtained 84 mg (87%) of a white powder. [a]20D= + 170 (c=0.5%, DMSO).
F~am~le 6. Preparation of (-)-~carbomethoxy-~methyl-2-~(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-ben7imidazole magnesium salt (-)-~carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-berl7imi~1~70le sodium salt (100 mg, 0.24 mmol) obtained as in Example 4 was dissolved in water (2 ml) and MgCl2x6H2O (25 mg, 0.12 mmol) dissolved in water (1 ml) was added dropwise. The formed precipitate was isolated by centrifugationand washed with water. ~he product was dried in a le~icc~tor and there was obtained 84 mg (87%) of a white powder.[a]20D= -178.8 (c=0.5%, DMSO).
~6~g WO 95/3295~ 13 PCTISE95/00~19 Table 1.
Ex. Solvent NMR data d ppm 1. DMS~d6 2.62 (s, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 300 MHz 4.68 (s, 2H), 7.09 (d, lH), 7.53 (s, lH), 8.11 (s, lH), 8.12 (d, lH), 13.75 (b, lH).
2. DMS~d6 2.62 (s, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 300 MHz 4.68 (s, 2H), 7.09 (d, lH), 7.53 (s, lH), 8.11 (s, lH), 8.12 (d, lH), 13.75 (b, lH).
NOVEL DIALKOXY-PYRIDINYL-BENZIMIDAZOLE DER~VATIVES
Field of the invention 5 The present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation. The invention also relates to novel intermediates in the preparation of the compounds of the invention.
Ba~ k~round of theinvention The compound 5-carbomethoxy-6-methyl-2-[[(3,~dimethoxy-2-pyridinyl)methyl]sulfinyl]-1~ benzimidazole, and therapeutically acceptable salts 15 thereof are described in application number EP 91911618.6. This compound and its therapeutically acceptable salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents. The compounds, being sulfoxides, have an asymrnetric center in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved 20 pharmacokinetic and metabolic properties which will give an improved therapeutic profile. The present ~ /enlion provides such compounds, which are novel salts of single enantiomers of 5-carbomethc-xy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1~ benzimidazole as well as the novel single enantiomers of the neutral form of said compound.
The separation of the enantiomers of therapeutically active sulfoxides, such as substituted ben7imi~1a70l~, for example omeprazole (5-methoxy-2-[[(~methoxy-3,5 dimethyl-2-pyridinyl)methyl]sulfinyl~ ben7imi~la7ole) in analytical scale isdescribed in e.g. J. Chromatography, 532 (1990), 30~19. The isolation of single 30 enantiomers of the sulfoxide agent Ro 18-5364 is described in Euro. J. Biochem. 166 `' (1987) 453-459. Furthermore, separation of the enantionlPr~ of omeprazole in a preparative scale is ~le~ rihed in DE 4035455. The latter has been done by using a diastereomeric ether which is separated and thereafter hydrolysed in an acidic solution. Under the acidic conditions needed for hydrolysis of the attached group, 35 the active compound, omeprazole, is quite sensitive and the acid has to be quickly WO 95/32959 ~ 1 ~ 6 ~ 2 PCT/SE95/00519 neutralized with a base to avoid degradation of the acid-sensitive compound. In the above mentioned application this is done by adding the reaction mixture containing concentrated sulfuric acid to a concentrated solution of NaOH. This is disadvantageous because there is a great risk of locally reaching pH values 5 between 1-6, which would be devastating for the substance. Moreover, instantaneous neutralization will create heat which will be difficult to handle in large scale production.
The present invention in a further aspect provides a novel method for preparing 10 the novel compounds of the invention in large scale. Thus, this novel method can be used in large scale to obtain single enantiomers of the compound of the invention in neutral form, as well as in the form of the therapeutically acceptable salts.
15 These novel compounds of the invention, being sulfoxides, could be expected to undergo racemization in neutral pH as well as in basic pH. See for example Brandstrom et al, Acta Chemica Scandinavia 43 (1989) p.536-547. Surprisingly, the inventors now found that the novel single enantiomers of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH ber~7imi~1~701e as well 20 as its therapeutically acceptable salts are stable towards racemi_ation.
There is no example known in the prior art of any isolated or characterized single enantiomers of the compound of the invention. Furthermore, the inventors are notaware of any description in the scientific literature of any isolated salt of a single 25 enantiomer of the rl~ime~l type.
Detailed description of the invention 30 The present invention refers to the new single enantiomers of 5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH benzimidazole according to compounds Ia and lb 6~g8~
~OCH3 I~N~CH2--~/ ~COOCH3 ~I Ib) r CH3 H
Ia (+)-enantiomer Ib (-)-enantiomer as well as therapeutically acceptable salts thereof. Such salts are for example the Na+, Mg2+, Ca2+, Li+, K+ and N+(R)4 salts of the single enantiomers of said compound, where R is an alkyl group with 1-4 carbon atoms, i.e. (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH
10 benzimidazole and (-)-5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH benzimidazole as well as Na+, Mg2+, Ca2+, Li+, K+
and N+(R)4 salts of the single enantiomers, where R is an alkyl group with 1-4 carbon atoms.
15 Particularly ~refel,~d salts of the compound of the invention are the Na+, Mg2+
and Ca2~~ salts of the single enantiomers of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole.
The mosl: preferred compounds of the invention are the optically pure 5-20 carbomethoxy-~methyl-2-[[(3,~dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH
benzimidazole according to the above formulas Ia and Ib. Further ~r~fe.led compounds are the optically pure Na+ salts of 5 carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole according to compounds IIa and Il[b W095t32959 ~G~ 4 PCT/SE95/OOS19 ~CH3 ~,OCH3 I~N~CH2--S~/ ~[~COOCH3 ~a IIb) Na+
IIa (+)-enantiomer IIb (-)-enantiomer 5 and the optically pure magnesium salts of said compounds having the formulas ma and IIIb.
~,OCH3 I~N~CH2--S~/ ~COOCH3 ~ma mb) Mg2+
ma (+)-enantiomer IIIb (-)-enantiomer With the expression "optically pure compound of the invention" is meant the (+)-enantiomer of said compound essentially free from the col,e~onding (-)-15 enantiomer and the (-)-enantiomer essentially free from the co~re~onding (+)-enantiom~r, respectively. Thus, every single compound of the invention is obtained in high optical purity. By means of the novel specific method accordingto one aspect of the invention of preparing the single enantiomers, the compounds of the invention are easy to obtain. Moreover, as mentioned above the novel 20 optically pure compounds are stable towards racemization in neutral pH as well as basic pH. The former was surprising since the mechanism of the degradation reactions at neutral pH of these kind of sulfoxides (omeprazole analogues) contains reversible reactions via achiral interme~liAtes (see e.g. Brandstrom et al.
Acta Chemica Scandinavica 43 (1989) 53~547, especially p.538). It is obvious that 25 such reversible reactions from achiral int~ liAtes back to a sulfoxide would 2~ I 6 6 ~ g ~ PCT/SE95/00519 cause a racemic product. Further, the novel optically pure compounds are stable towards racemization in basic pH, which was surprising sirlce the known deprotonation at the carbon atom between the pyridine ring and the chiral sulphur atom was expected to cause racemization under alkaline conditions. This 5 high stability towards r~c~mi7~tion, both in neutral pH and basic pH, makes itpossible to use a single enantiomeric compound of the invention in the neutral form as well as salts thereof in therapy.
The specific method of preparation of the single enantiomers of the compound of 10 the invention is a further aspect of the invention as mentioned above and it can be used to obtain the single enantiomeric compounds in the neutral form as well as the salts thereof.
The single enantiomeric compounds of the invention as well as the racemate have 15 a high level of bioavailability, and does not block the uptake of iodine into the thyroid gland, and still said compounds are very effective as inhibitors of gastric acid secretion and exhibit high stability properties at neutral pH.
The compounds according to the invention may be used for inhibiting gastric acid20 secretion in nl~mm~l~ and man. In a more general sense, the single enantiomeric compounds of the invention may be used for the treatment of gastric acid-relateddiseases and gastrointestinal inflammatory diseases in ~mm~l~ and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis. Furthermore, the compou~nds may be used for treatment of other gastrointestinal disorders where 25 gastric antise~leloly effect is desirable e.g. in patients on NSAID therapy, in patients with gastrinomas, and in patients with accute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration. The compourld of the invention may also be used for treatment or prophylaxis of 30 inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be sepcifically mentioned are rheumatoid arthritis and gout. The compound of the invention may also be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections.
35 Yet a further aspect of the invention is the diasteromeric mixture of a regioi~omeric mixture having the formula IV, which is an intermediate used in the WO 95132959 ~ 6 PCT/SE95/00519 specific method of preparation, wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in the 5 or 6 position, respectively.
,OCH3 ~,OCH3 I~N~CH2--S~/ ~COOCH3 N CH3 (IV) O
Preparation The optically pure compounds of the invention, i.e. the single enantiomers, are prepared by separating the stereoisomers of a diastereom~ric mixture of the 10 regioisomeric mixture of the following type, 5-carbomethoxy-6-methyl-2-[[(3,~
dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-l(R)-acyloxymethyl-lH-be~7imi~ole and 6-carbomethoxy-5-methyl-2-[[(3,~dimethoxy-2-pyridinyl)methyl]-(R/s)-sulfinyl]-l-[(R)-acyloxymethyl-l~I-benzimidazole formula V
~,OCH3 I~N~CH2--S~/ ~ COOCH3 N CH3 (V) CH2--OAcyl wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in position 5 or 6, respectively, and wherein the Acyl radical is as defined20 below, followed by a solvolysis of each separated diastereomer in an alkalinesolution. The formed single enantiomeric compounds of the invention in neutral form are then isolated by neutralizing aqueous solutions of the salts of said wo 9s/32959 7 ~ ~ ~ 6 ~ ~ ~ PCT/SE95/00519 compounds with a neutralizing agent which can be an acid or an ester such as methyl formate.
The Acyl moiety in the diastereomeric ester may be a chiral acyl group such as 5 mandeloyl, and the asymmetric center in the chiral acyl group can have either R or S configuration.
The diastereomeric esters can be separated either by chromatography or fractional crystallization.
The solvolysis usually takes place together with a base in a protic solvent such as alcohols or water; or with a base in a mixture of acetonitrile and water, but the acyl group may also be hydrolysed off by a base in an aprotic solvent such as dimethylsulfoxide or dimethylformamide. The reacting base may be OH- or R1O-15 where R1 can be any alkyl or aryl group.
To obtain the optically pure Na+ salts of the invention, i.e. Na+ salts of the s ingleenantiomeric compound of the invention, the resulting compound in neutral form is treated with a base, such as NaOH, in an aqueous or nonaqueous medium, or 20 with NaOR2 wherein R2 is an alkyl group containing 1-4 carbon atoms, or with NaNH2. Also alkaline salts wherein the cation is Li+ or K+ may be prepared usinglithium or potassium salts of the above mentioned bases. In order to obtain the crystalli~e form of the single enar~tiom~rs of the Na+ salts, to the optically pure Na+ salts as a syrup are added a mixture of 2-butanone and toluene, but the 25 crystalline form of the single enantiomers of the Na+ salt may also be prepared by adding NaOH to a mixture of the single enantiomeric compound of invention and a non-aqueous medium, such as a mixture of 2-butanone and toluene.
To obtain the optically pure Mg2+ salts of the invention, optically pure Na+ salts 30 are treated with an aqueous solution of an inorganic magnesium salt such as MgC12, whereupon the Mg2+ salts are precipitated. The optically pure Mg2+ salts may also be prepared by treating single enantiomeric compound of the invention with a baLse, such as Mg(oR3)2, wherein R3 is an alkyl group containing 1-4 carbon atoms, ir~ a non-aqueous solvent such as alcohol (only for alcoholates), e.g. ROH, 35 or in an ether such as tetrahydrofuran. In an analogous way, also alkaline salts wherein the cation is Ca2+ can be prepared, using an aqueous solution of an inorganic c~ m~ salt such as CaCk.
wo 95/32959 ~ 5 8 PCT/SE9S/00519 Alkaline salts of the single enantiomers of the invention are, as mentioned above, beside the sodium salts (compounds IIa and IIb) and the magnesium salts (compound ma and mb), exemplified by their salts with Li+, K+, Ca2+ and N+(Rj4, where R is an alkyl group with 1-4 C-atoms.
Por clinical use the single enantiomers, i.e. the optically pure compounds, of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other modes of administrations. The pharmaceutical formulations contain the single enantiomers of the invention normally in combination with a 10 pharmaceutically acceptable carrier. The carrier may be in form of a solid, semi-solid or liquid diluent, or capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1-95% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1-50% by weight in preparations for oral 15 adrninistration. An active compound in a form with high solubility in water is requested for parenteral preparations, for some oral preparations an active compound in a form with low solubility is suitable.
In the preparation of pharmaceutical formulations in form of dosage units for oral 20 administration the single enantiomeric compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, c~ lose derivates, gelatin or another suitable carrier, stabilizingsubstances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating 25 agents such as magnesium stearate, c~l~ itlm stearate, sodium stearyl fumarate and polyethylenglycol waxes. The mixture is then processed into granules or pressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalysed degradation as long as the dosage form remair~s in the stomach. The enteric coating is chosen among 30 pharmaceutically acceptable enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers and the like, if ~reL~Lled in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different amounts of the active compound present.
35 Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound, vegetable oil, fat, or other suitable vehicle for soft gelatinecapsules. Soft gelatine capsules may also be enteric-coated as described above.
wo gs/3295g 9 2 ~ 8 8 PCT/SEg~/00519 Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, 5 mannitol, potato starch, amylopectin, cellulose derivates or gelatin. The capsules may be enteric-coated as described above.
Dosage ~nits for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or 10 they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to 15 administration.
Liquid preparation for oral administration may be prepared in the form of syrupsor suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight o~ the active ingredient and the remainder consisting of sugar or sugar 20 alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of dry powder to be reconstituted with a suitable solvent 25 prior to use.
Solutions for parenteral administrations may be prepared as solutions of the single enantiomeric compounds of the invention in pharmaceutically acceptable solvents, ~refelably in a concentration from 0.1 to 10% by weight. These soultions may also 30 contain stabilizing agents and/or buffering agents and may be manufactured indifferent unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as dry preparations to be reconsituted with a suitable solvent extemporaneously before use.
35 The typical daily dose of the active compound will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of acti~e substance.
The invention is illustrated by the follo~ring examples.
F.xample 1. Preparation of (+)-5-carbomethoxy-~methyl-2-~(3 4-dimethoxy-2-pvridinyl)methyl]sulfinyl]-lH-ben7.imidazole 10 The crude product of the diastereomers of a mixture of two regioisomeric mandelic esters, namely 5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-l(R)-mandeloyloxymethyl]-lH-benzimidazole and ~carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-lH-benzimidazole (1.8 g, 3.3 mmol) was 15 divided into three parts. Each part was chromatographed on a reversed phase column (HPLC, Kromasil C8) in order to separate the diastereomers. The stereoisomers were easily separated by elution with a mixture of aqueous 0.1 M
ammonium acetate and acetonitrile (70/30), but each separated diastereomer consisted of a mixture of the two regioisomers. These intermediates were used 20 directly in their solutions during the hydrolyses; To the acetonitrile/aqueous solutiorls of the more lipophilic diastereomer were added 1 M aqueous solutions of NaOH until the pH was around 12-13. After 5 minutes the solutions were neutralized with 3.0 M aqueous solutions of NH4Cl. The solutions from each preparation were combined and extracted with methylenechloride whereupon the 25 organic phases were dried over Na2SO4. Removal of the solvents and flash chromatography of the residue (silica gel, methanol-methylenechloride gradient 1-8%) yielded 250 mg of a yellow oil. The product was crystallised by adding acetonitrile (3 ml) and after filtration there was obtained 210 mg (32%) of the title compound as white crystals m.p. 171-173 C. [a]20 D= +153.1 (c=0.5%, 30 chlorofo~
NMR data are given below.
WO 95/32959 ~ fi ~ PCT/SE95/00519 E~xample 2. Preparation of (-)-5-carbomethoxy-~methyl-2-[[(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole To the acetonitrile/aqueous solutions of the less lipophilic diastereomer of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-l_-benzimidazole and 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-lH-benzimidazole (obtained from the very same reversed phase chromatographic preparations described in Example 1) were added 1.0 M NaOH until the pH was around 12-13. After 5 minutes the solutions were neutralized with 3.0 M aqueous solutions of NH4Cl. The solutions from each preparation were combined and extracted with methylenechloride whereupon the organic phases were dried over Na2SO4. Removal of the solvents and flash chromatography of the residue (silica gel, methanol-methylenechloride gradient 1-8%) yielded 270 mg of a yellow oil.
The product was crystallized by adding acetonitrile (3 ml) and after filtration there was obtained 210 mg (32%) of the title compound as white crystals m.p. 173-174 C. [a]20D= -150.0 (c=0.5%, chloroform).
NMR data are given below.
Fxample 3. Preparation of (+)-5-carbomethoxy-6-methyl-2-~(3.~dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-be~7imidazole sodium salt To a mixture of (+)-5-carbomethoxy~methyl-2-[[(3,~dimethoxy-2-pyridinyl)-methyl]sulfinyl]-l-~-benzimidazole (200 mg,0.51 mmol) and ethanol (10 ml) was added an aqueous solution of 2.0 M NaOH (0.26 ml, 0.51 mmol). The solvent wa removed by film evaporation whereupon the residue was dissolved in 2-butanone (1 ml). Toluene (5 ml) was added dropwise while stirring. The formed precipitatewas removed by centrifugation and washed with diethyl ether. There was obtained 170 mg (81%) of the title compound as white crystals m. p. (decomp.) 170-173C. [a]20D= +93.6(c=1%, methanol).
.
NMR data are given below g~ --Fxample 4. Preparation of (-)-5-carbomethoxy-~methyl-2-[[(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1~-benzimidazole sodium salt To a mixture of (-)-5-carbomethoxy-~methyl-2-[[(3,4-dimethoxy-2-pyridinyl)-methyl]sulfinyl]-1-~-benzimidazole (200 mg, 0.51 mmol) and ethanol (10 ml) was added an aqueous solution of 2.0 M NaOH (0.26 ml, 0.51 mmol). The solvent was removed by film evaporation whereupon the residue was dissolved in 2-butanone (2 ml). Toluene (5 ml) was added dropwise while stirring. The formed precipitatewas isolated by filtration and washed with diethyl ether. There was obtained 200mg (96%) of the title compound as white crystals m. p. (decomp.) 172-175C.
[a]20D= -93.8 (c=1%, methanol).
NMR data are given below F~xample 5. Preparation of (+)-~carbomethoxy-~methyl-2-~[(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl~-lH-benzimidazole magnesium salt (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-~-benzimidazole sodium salt (100 mg, 0.24 mmol) obtained as in Example 3 was dissolved in water (2 ml) and MgCkx6H20 (25 mg, 0.12 mmol) dissolved in water (1 ml) was added dropwise. The formed precipitate was isolated by centrihlgationand washed with water. The product was dried in a desiccator and there was obtained 84 mg (87%) of a white powder. [a]20D= + 170 (c=0.5%, DMSO).
F~am~le 6. Preparation of (-)-~carbomethoxy-~methyl-2-~(3 4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-ben7imidazole magnesium salt (-)-~carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-berl7imi~1~70le sodium salt (100 mg, 0.24 mmol) obtained as in Example 4 was dissolved in water (2 ml) and MgCl2x6H2O (25 mg, 0.12 mmol) dissolved in water (1 ml) was added dropwise. The formed precipitate was isolated by centrifugationand washed with water. ~he product was dried in a le~icc~tor and there was obtained 84 mg (87%) of a white powder.[a]20D= -178.8 (c=0.5%, DMSO).
~6~g WO 95/3295~ 13 PCTISE95/00~19 Table 1.
Ex. Solvent NMR data d ppm 1. DMS~d6 2.62 (s, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 300 MHz 4.68 (s, 2H), 7.09 (d, lH), 7.53 (s, lH), 8.11 (s, lH), 8.12 (d, lH), 13.75 (b, lH).
2. DMS~d6 2.62 (s, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 300 MHz 4.68 (s, 2H), 7.09 (d, lH), 7.53 (s, lH), 8.11 (s, lH), 8.12 (d, lH), 13.75 (b, lH).
3. DMS~d6 2.58 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 300 MHz 4.36 (d, lH), 4.74 (d, lH), 7.07 (d, lH), 7.31 (s, lH), 8.10 (s, lH), 8.21 (d, lH).
4. DMS~d6 2.58 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 300 MHz 4.34 (d, lH), 4.74 (d, lH), 7.07 (d, lH), 7.29 (s, lH), 8.11 (s, lH), 8.22 (d, lH).
Preparation of the synthetic intermediates according to the invention will be described in the following example.
F.xample 7. Preparation of 5-carbomethoxy-6-methyl-2-~(3 4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-lH-benzimidazole and 6-carbomethoxy-5-methyl-2-~(3 4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl] l-[(R)-mandeloyloxymethyl]-lH-benzimidazole A solution of 0.33 g (8.2 mmol) sodium hydroxide in 1.6 ml water was added to a mixture of 1.4 g (4.1 mmol) tetrabutylammonium hydrogen sulfate and 0.62 g (4.1 mmol) of (R)-(-)-mandelic acid. Chlor~ro~ (50 ml) and a mixture of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]-1-(chloromethyl)-lH-ben_imidazole and 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-l-(chloromethyl)-lH-be~7imi~lA70le (as racemates) were added and the mixture was refluxed for 3 hours. The reaction mixture was chilled and then partitioned between ethyl acetate and water. The wo ss/329sg ~, ~ 6 ~ ~ ~ 14 PCT/SE95/00519 layers were separated and the organic phase was washed with water and dried over Na2SO4. Removal of solvents yielded a diastereomeric mixture of the two regioisomeric mandelic esters. The crude product was used directly in the chromatographic step where the diastereomers were separated (Example 1 and 2).
Preparation of the synthetic intermediates according to the invention will be described in the following example.
F.xample 7. Preparation of 5-carbomethoxy-6-methyl-2-~(3 4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl]-l-[(R)-mandeloyloxymethyl]-lH-benzimidazole and 6-carbomethoxy-5-methyl-2-~(3 4-dimethoxy-2-pyridinyl)methyl]-(R/S)-sulfinyl] l-[(R)-mandeloyloxymethyl]-lH-benzimidazole A solution of 0.33 g (8.2 mmol) sodium hydroxide in 1.6 ml water was added to a mixture of 1.4 g (4.1 mmol) tetrabutylammonium hydrogen sulfate and 0.62 g (4.1 mmol) of (R)-(-)-mandelic acid. Chlor~ro~ (50 ml) and a mixture of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]-1-(chloromethyl)-lH-ben_imidazole and 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-l-(chloromethyl)-lH-be~7imi~lA70le (as racemates) were added and the mixture was refluxed for 3 hours. The reaction mixture was chilled and then partitioned between ethyl acetate and water. The wo ss/329sg ~, ~ 6 ~ ~ ~ 14 PCT/SE95/00519 layers were separated and the organic phase was washed with water and dried over Na2SO4. Removal of solvents yielded a diastereomeric mixture of the two regioisomeric mandelic esters. The crude product was used directly in the chromatographic step where the diastereomers were separated (Example 1 and 2).
5 Yield: 2.4 g, 62%.
NMR data are given below.
Table 2.
Solvent N~Rdata dppm 7. CDC13 2.6-2.8 (m, 3H), 3.8-4.1 (m, 9H), 4.75-4.95 (m, lH), 500 MHz 5.00-5.15 (m, lH), 5.~5.4 (m, lH), 6.45-6.70 (m, 2H), 6.70-6.80 (m, lH), 7.1-8.4 (m, 8H).
The best mode of carrying out the invention known at present is to use the magnesium salts of the optically pure compounds of the invention, thus the compounds described in Examples 5 and 6.
P~ ceutical preparations containing the compounds of the invention as active ingredient are illustrated in the following formulations.
25 Syrup A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
Compound according to Example 1 1.0 g Sugar, powder 30.0 g Saccharine 0.6 g Glycerol 5.0 g Flavouring agent 0.05 g Ethanol96% 5.0 g Distilled water q.s. to a final volume of 100 ml WO 95/32959 15 ~ ~ S ~ PCT/SE95/00519 Sugar and saccharine were dissolved in 60 g of warm water. After cooling the active compound was added to the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.
Enteric-coated tablets An enteric coated tablet containing 50 mg of active compound was prepared from 10 the following ingredients:
Compound according to Example 2 500 g Lacl:ose 700 g Methyl cellulose 6 g Polyvinylpyrrolidone cross-linked 50 g Magnesium stearate 15 g Sodiu~n carbonate 6 g Distilled water q.s.
~ Cellulose acetate phthalate 200 g Cetyl alcohol 15 g Isopropanol 2000 g Methylene chloride 2000 g 25 I Compound according to Example 2, powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet mass was forced through a sieve and the granulate dried in an oven. After drying the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was pressed into tablet cores (10 000 tablets), each tablet 30 containing 50 mg of active substance, in a tabletting machine using 7 mm diameter punches.
II A solution of cPlll~lose acetate phthalate and cetyl alcolhol in isopropanol/methylene chloride was sprayed onto the tablets I in an Accela 35 CotaR, Manesty coating equipment. A final tablet weight of 110 mg was obtained.
WO 95/329~i9 16 PCT/SE95/OOSl9 Solution for intravenous administration A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients:
Compound according to Example 3 4 g Sterile water to a final volume of 1000 ml The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a 0.22 llm filter and immediately dispensed into 10 ml sterile ampoules. The ampoules were sealed.
Capsules Capsules containing 30 mg of active compound were prepared from the following ingredients:
Compound according to Example 6 300 g ~ ~ctose 700 g Microcrystalline cellulose 40 g Hydroxypropyl cellulose low-substituted 62 g Disodium hydrogen phosphate 2 g Purified water q.s.
The active compound was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate. The wet mass was forced through an extruder and spheronized and dried in a fl~ i7e~i bed dryer.
30 500 g of the pellets above were first coated with a solution of hydroxypropylmethylcellulose, 30 g, in water, 750 g, using a fl~ erl bed coater. After drying, the pellets were coated with a second coating as given below:
W0 95/32959 ~ PCT/SE95/00519 Coating solution:
Hydroxypropyl methylcellulose phthalate 70 g Cetyl alcohol 4 g Acetone 200g Ethanol 600 g The final coated pellets were filled into capsules.
Suppositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
Compound according to Example 2 4 g Witepsol H-15 180 g The active compound was homogenously mixed with Witepsol H-15 at a temperature of 41 C. The molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed. Each suppository contained 40 mg of active compound.
Stability towards racemization at different pH:es The stability of the optically pure compounds of the invention towards r2cPmi7~tion has been measured at low concentrations (10-5 M) at 37C in aqueousbuffer solutions at pH 7 and pH 11. The stereo chemic~l stability was measured by comparing the optical purity for the (-)-enantiomer of 5-carbomethoxy-~methyl-2-[[(3,4-dirnethoxy-2-pyridinyl)methyl]sulfinyl]-1-~-benzimidazole in buffer solution imme~ tely after dissolving and after several hours. The surprising high stereo chemi~l stability in neutral conditions as well as in alkaline conditions for the compounds of invention is exemplified by the fact that no racemi7~tion for the test compound was obtained neither at pH 7 nor at pH 11, even after 24 hours. AtpH 7, however, the chemical degradation of the compound is much apparent after 28 hours.
NMR data are given below.
Table 2.
Solvent N~Rdata dppm 7. CDC13 2.6-2.8 (m, 3H), 3.8-4.1 (m, 9H), 4.75-4.95 (m, lH), 500 MHz 5.00-5.15 (m, lH), 5.~5.4 (m, lH), 6.45-6.70 (m, 2H), 6.70-6.80 (m, lH), 7.1-8.4 (m, 8H).
The best mode of carrying out the invention known at present is to use the magnesium salts of the optically pure compounds of the invention, thus the compounds described in Examples 5 and 6.
P~ ceutical preparations containing the compounds of the invention as active ingredient are illustrated in the following formulations.
25 Syrup A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
Compound according to Example 1 1.0 g Sugar, powder 30.0 g Saccharine 0.6 g Glycerol 5.0 g Flavouring agent 0.05 g Ethanol96% 5.0 g Distilled water q.s. to a final volume of 100 ml WO 95/32959 15 ~ ~ S ~ PCT/SE95/00519 Sugar and saccharine were dissolved in 60 g of warm water. After cooling the active compound was added to the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.
Enteric-coated tablets An enteric coated tablet containing 50 mg of active compound was prepared from 10 the following ingredients:
Compound according to Example 2 500 g Lacl:ose 700 g Methyl cellulose 6 g Polyvinylpyrrolidone cross-linked 50 g Magnesium stearate 15 g Sodiu~n carbonate 6 g Distilled water q.s.
~ Cellulose acetate phthalate 200 g Cetyl alcohol 15 g Isopropanol 2000 g Methylene chloride 2000 g 25 I Compound according to Example 2, powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet mass was forced through a sieve and the granulate dried in an oven. After drying the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was pressed into tablet cores (10 000 tablets), each tablet 30 containing 50 mg of active substance, in a tabletting machine using 7 mm diameter punches.
II A solution of cPlll~lose acetate phthalate and cetyl alcolhol in isopropanol/methylene chloride was sprayed onto the tablets I in an Accela 35 CotaR, Manesty coating equipment. A final tablet weight of 110 mg was obtained.
WO 95/329~i9 16 PCT/SE95/OOSl9 Solution for intravenous administration A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients:
Compound according to Example 3 4 g Sterile water to a final volume of 1000 ml The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a 0.22 llm filter and immediately dispensed into 10 ml sterile ampoules. The ampoules were sealed.
Capsules Capsules containing 30 mg of active compound were prepared from the following ingredients:
Compound according to Example 6 300 g ~ ~ctose 700 g Microcrystalline cellulose 40 g Hydroxypropyl cellulose low-substituted 62 g Disodium hydrogen phosphate 2 g Purified water q.s.
The active compound was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate. The wet mass was forced through an extruder and spheronized and dried in a fl~ i7e~i bed dryer.
30 500 g of the pellets above were first coated with a solution of hydroxypropylmethylcellulose, 30 g, in water, 750 g, using a fl~ erl bed coater. After drying, the pellets were coated with a second coating as given below:
W0 95/32959 ~ PCT/SE95/00519 Coating solution:
Hydroxypropyl methylcellulose phthalate 70 g Cetyl alcohol 4 g Acetone 200g Ethanol 600 g The final coated pellets were filled into capsules.
Suppositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
Compound according to Example 2 4 g Witepsol H-15 180 g The active compound was homogenously mixed with Witepsol H-15 at a temperature of 41 C. The molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed. Each suppository contained 40 mg of active compound.
Stability towards racemization at different pH:es The stability of the optically pure compounds of the invention towards r2cPmi7~tion has been measured at low concentrations (10-5 M) at 37C in aqueousbuffer solutions at pH 7 and pH 11. The stereo chemic~l stability was measured by comparing the optical purity for the (-)-enantiomer of 5-carbomethoxy-~methyl-2-[[(3,4-dirnethoxy-2-pyridinyl)methyl]sulfinyl]-1-~-benzimidazole in buffer solution imme~ tely after dissolving and after several hours. The surprising high stereo chemi~l stability in neutral conditions as well as in alkaline conditions for the compounds of invention is exemplified by the fact that no racemi7~tion for the test compound was obtained neither at pH 7 nor at pH 11, even after 24 hours. AtpH 7, however, the chemical degradation of the compound is much apparent after 28 hours.
Claims (20)
1. Single enantiomeric compounds having the formula Ia and Ib (Ia,Ib) Ia (+)-enantiomer Ib (-)-enantiomer and the therapeutically acceptable salts thereof.
2. Compounds according to claim 1 c h a r a c t e r i z e d in that the compound is (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or a therapeutically acceptable salt thereof, substantially free of its (-)-enantiomer.
3. Compounds according to to claim 1 c h a r a c t e r i z e d in that the compound is (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole, or a therapeutically acceptable salt thereof, substantially free of its (+)-enantiomer.
4. Compounds according to any of claims 1-3 c h a r a c t e r i z e d in that the therapeutically acceptable salts are Na+, Mg2+, Ca2+, Li+, K+ and N+(R)4 salts wherein R is an alkyl group with 1-4 carbon atoms.
5. Compounds according to any of claims 1-4 c h a r a c t e r i z e d in that the compounds are (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole sodium salt, (-)-5-carbomethoxy-6-methyl-2-1[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole sodium salt, (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole magnesium salt and (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole magnesium salt.
6. Compounds according to any of claims 1-3 c h a r a c t e r i z e d in that the compounds are (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or its magnesium salt and (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or its magnesium salt, in their crystalline forms.
7. Compounds according to claims 1 and 2 c h a r a c t e r i z e d in that the compound is (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or the magnesium salt thereof, respectively, in its crystalline form substantially free of its (-)-enantiomer.
8. Compounds according to claims 1 and 3 c h a r a c t e r i z e d in that the compound is (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or the magnesium salt thereof, respectively, in its crystalline form substantially free of its (+)-enantiomer.
9. Process for the preparation of a compound according to claim 1 c h a r a c t e r i z e d in that a diastereomeric ester of formula V
(V) wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in the 5 or 6 position, respectively, and wherein Acyl designates a chiral acyl group such as mandeloyl, having either R or S configuration, is separated, and each of the separated diastereomers is subjected to solvolysis with an alkaline solution where the acyloxymethyl group is hydrolyzed off to give the enantiomeric compound in neutral form after neutralization with a neutralizing agent whereupon the enantiomeric compound in neutral form optionally is converted into a therapeutically acceptable salt.
(V) wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in the 5 or 6 position, respectively, and wherein Acyl designates a chiral acyl group such as mandeloyl, having either R or S configuration, is separated, and each of the separated diastereomers is subjected to solvolysis with an alkaline solution where the acyloxymethyl group is hydrolyzed off to give the enantiomeric compound in neutral form after neutralization with a neutralizing agent whereupon the enantiomeric compound in neutral form optionally is converted into a therapeutically acceptable salt.
10. Process according to claim 9 c h a r a c t e r i z e d in that the diastereomers are separated by chromatography or fractional crystallization.
11. Process according to claim 9 c h a r a c t e r i z e d in that the solvolysis is performed in an alkaline solution consisting of a base in a protic solvent, such as alcohols or water; or a base in an aprotic solvent, such as dimethylsulfoxide ordimethylformamide; or a base in a mixture of protic and aprotic solvents, such as water and acetonitrile.
12. Process for the preparation of a compound according to any of claims 1-4 in crystalline form c h a r a c t e r i z e d in that a product obtained in claim 9 either neutral form or in the form of a therapeutically salt is treated with a non-aqueous solvent to precipitate the product.
13. Process for preparation of (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or its sodium salt and (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or its sodium salt in their crystalline forms c h a r a c t e r i z e d in that (+)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or its sodiurn salt and (-)-5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-H-benzimidazole or its sodium salt crude product, respectively is treated with a non-aqueous medium, such as 2-butanone and toluene.
14. Pharmaceutical preparation comprising single enantiomeric compound according to any of claims 1-8 as active ingredient.
15. Single enantiomeric compounds according to any of claims 1-8 for use in therapy.
16. Use of a single enantiomeric compound according to any of claims 1-8 in the manufacture of a pharmaceutical formulation for inhibiting gastric acid secretion.
17. Use of a single enantiomeric compound according to any of claims 1-8 for themanufacture of a pharmaceutical formulation for the treatment of gastrointestinal inflammatory diseases.
18. A method for inhibiting gastric acid secretion comprising administration to a mammal including man in need of such treatment an effective amount of an enantiomeric compound according to any of claims 1-8.
19. A method for the treatment of gastrointestinal inflammatory diseases comprising administration to a mammal including man in need of such treatment an effective amount of an enantiomeric compound according to any of claims 1-8.
20. The compounds 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-[mandeloyloxymethyl]-1H-benzimidazole and carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-[mandeloyloxymethyl]-1H-benzimidazole.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9400511 | 1994-05-27 | ||
| WOPCT/SE94/00511 | 1994-05-27 | ||
| PCT/SE1995/000519 WO1995032959A1 (en) | 1994-05-27 | 1995-05-11 | Novel dialkoxy-pyridinyl-benzimidazole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2166988A1 true CA2166988A1 (en) | 1995-12-07 |
Family
ID=20392945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166988A Abandoned CA2166988A1 (en) | 1994-05-27 | 1995-05-11 | Novel dialkoxy-pyridinyl-benzimidazole derivatives |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0712401A1 (en) |
| JP (1) | JPH09504557A (en) |
| CN (1) | CN1128997A (en) |
| AU (1) | AU2633095A (en) |
| BR (1) | BR9506235A (en) |
| CA (1) | CA2166988A1 (en) |
| CZ (1) | CZ24396A3 (en) |
| EE (1) | EE9600011A (en) |
| FI (1) | FI960367A0 (en) |
| HU (1) | HU9600005D0 (en) |
| IL (1) | IL113604A0 (en) |
| IS (1) | IS4321A (en) |
| MA (1) | MA23563A1 (en) |
| NO (1) | NO960268L (en) |
| PL (1) | PL312692A1 (en) |
| TN (1) | TNSN95062A1 (en) |
| WO (1) | WO1995032959A1 (en) |
| ZA (1) | ZA954125B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9423970D0 (en) * | 1994-11-28 | 1995-01-11 | Astra Ab | Oxidation |
| GB9423968D0 (en) * | 1994-11-28 | 1995-01-11 | Astra Ab | Resolution |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| ES2222754T3 (en) * | 1998-11-18 | 2005-02-01 | Astrazeneca Ab | IMPROVED CHEMICAL PROCEDURE, AND PHARMACEUTICAL FORMULATION. |
| US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| WO2008057802A2 (en) | 2006-10-27 | 2008-05-15 | The Curators Of The University Of Missouri | Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same |
| CN101980700A (en) | 2008-02-20 | 2011-02-23 | 密苏里大学董事会 | Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same |
| CA2736547C (en) | 2008-09-09 | 2016-11-01 | Pozen Inc. | Method for delivering a pharmaceutical composition to patient in need thereof |
| AU2010263304A1 (en) | 2009-06-25 | 2012-02-02 | Astrazeneca Ab | Method for treating a patient at risk for developing an NSAID-associated ulcer |
| UA115139C2 (en) | 2011-12-28 | 2017-09-25 | Поузен Інк. | Improved compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69131627T2 (en) * | 1990-06-20 | 2000-04-27 | Astra Ab Soedertaelje | DIALKOXYPYRIDINYLBENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION AND THEIR PHARMACEUTICAL USE |
| DE4035455A1 (en) * | 1990-11-08 | 1992-05-14 | Byk Gulden Lomberg Chem Fab | ENANTIOMER SEPARATION |
-
1994
- 1994-05-29 TN TNTNSN95062A patent/TNSN95062A1/en unknown
-
1995
- 1995-05-03 IL IL11360495A patent/IL113604A0/en unknown
- 1995-05-11 PL PL95312692A patent/PL312692A1/en unknown
- 1995-05-11 WO PCT/SE1995/000519 patent/WO1995032959A1/en not_active Application Discontinuation
- 1995-05-11 BR BR9506235A patent/BR9506235A/en not_active Application Discontinuation
- 1995-05-11 EE EE9600011A patent/EE9600011A/en unknown
- 1995-05-11 CA CA002166988A patent/CA2166988A1/en not_active Abandoned
- 1995-05-11 CZ CZ96243A patent/CZ24396A3/en unknown
- 1995-05-11 JP JP8500730A patent/JPH09504557A/en active Pending
- 1995-05-11 EP EP95921187A patent/EP0712401A1/en not_active Withdrawn
- 1995-05-11 HU HU9600005A patent/HU9600005D0/en unknown
- 1995-05-11 CN CN95190482A patent/CN1128997A/en active Pending
- 1995-05-11 AU AU26330/95A patent/AU2633095A/en not_active Abandoned
- 1995-05-19 ZA ZA954125A patent/ZA954125B/en unknown
- 1995-05-26 MA MA23901A patent/MA23563A1/en unknown
-
1996
- 1996-01-17 IS IS4321A patent/IS4321A/en unknown
- 1996-01-23 NO NO960268A patent/NO960268L/en unknown
- 1996-01-26 FI FI960367A patent/FI960367A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995032959A1 (en) | 1995-12-07 |
| BR9506235A (en) | 1997-08-12 |
| ZA954125B (en) | 1995-11-27 |
| CN1128997A (en) | 1996-08-14 |
| PL312692A1 (en) | 1996-05-13 |
| EE9600011A (en) | 1996-04-15 |
| EP0712401A1 (en) | 1996-05-22 |
| IS4321A (en) | 1996-01-17 |
| NO960268D0 (en) | 1996-01-23 |
| HU9600005D0 (en) | 1996-03-28 |
| MA23563A1 (en) | 1995-12-31 |
| AU2633095A (en) | 1995-12-21 |
| NO960268L (en) | 1996-01-23 |
| JPH09504557A (en) | 1997-05-06 |
| CZ24396A3 (en) | 1996-06-12 |
| FI960367A (en) | 1996-01-26 |
| TNSN95062A1 (en) | 1996-02-06 |
| IL113604A0 (en) | 1995-08-31 |
| FI960367A0 (en) | 1996-01-26 |
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